Plasmodium falciparum malaria is one of the most important infectious diseases affecting the human population and is a multi-factorial process influenced by both parasite virulence factors and host genetic susceptibility. Rosetting and cytoadherence are believed to be the prime virulence factors involved in severe disease, and disruption of rosettes could be an important tool for treatment. The parasite ligand for rosette formation is a var gene product, PfEMP-1, that interacts with complement receptor one (CR1) on uninfected red cells. This proposal Will test the hypothesis that red cell CR1 is important in rosetting and malaria pathogenesis and that unique CR1-specific genetic polymorphisms have evolved in malaria endemic regions to confer resistance to severe disease. CR1 exhibits both quantitative (expression) and qualitative (Knops blood group) polymorphisms that differ significantly in frequency in malaria endemic vs. non-malarial regions. Red cells with low expression of CR1 have reduced rosetting while those negative for a Knops blood group antigen, Sla, formed fewer rosettes using PfEMP-1 expressing COS cells. Studies have shown that antibodies to rosettes are acquired with age and malaria immunity. Thus, any or all of these factors may protect from severe malaria. The molecular basis of the Knops antigens SIa, VII, McCa and MCCb were identified in order to genotype a large DNA database from malaria patients and correlate the Knops type with disease severity. However, the genotyping methods proved inadequate due to unforeseen variation in red cell CR1 expression resulting in discordant CR1 genotype and red cell phenotype. Thus, we propose to prospectively test patients whose red cells have normal CR1 levels but carry the Knops blood group polymorphisms to examine if they are functionally deficient and have a reduced avidity of binding between CR1 and its ligands (PfEMP-1). We will test patients with low red cell CR1 to determine if they are protected from syndromes involving micro-vascular obstruction (cerebral malaria) due to the inhibitory effect on rosetting. We will further determine if low red cell CR1 levels increase susceptibility to severe malaria anemia due to reduced protection of the red cells from complement damage. By defining the molecular basis and functional consequences of these CR1 polymorphisms we will have a better understanding of the host-parasite interactions in order to develop new therapeutics and provide better treatment.